Pulmonary hypertension (referred hereafter as PH) either occurs as a complication of various pathological conditions or is a primary disease for which no underlying cause can be found (Rubin 1997). Persistent vasoconstriction and structural remodeling of the pulmonary vessels are cardinal features of PH (Wagenvoort and Wagenvoort 1970). The origin of this disease, however, remains largely unknown. Evidence was recently provided that serotonin (5-hydroxytryptamine, hereafter referred as 5-HT) plays a major role in the pathogenesis of PH (Herve, Drouet et al. 1990). Indeed, 5-HT causes vasoconstriction through its binding to different types of 5-HT receptors expressed by pulmonary smooth muscle cells, namely 5-HT2 and 5-HT1B/1D receptors (Choi and Maroteaux 1996; MacLean, Sweeney et al. 1996). In addition, 5-HT exerts potent mitogenic and comitogenic effects on pulmonary artery smooth muscle cells (PA-SMCs) which require its internalization by a high affinity and selective transporter (5-HTT) (Lee, Wang et al. 1991; Lee, Wang et al. 1994; Eddahibi, Fabre et al. 1999). The 5-HTT is abundantly expressed in the lung (Ramamoorthy, Bauman et al. 1993) and is the target of appetite suppressant drugs reported to increase the risk of primary PH (Brenot, Herve et al. 1993; Abenhaim, Moride et al. 1996). In recent studies performed on lung tissues and pulmonary arteries from patients with primary PH who underwent lung transplantation, it was discovered that the disease was associated with an increased expression of 5-HTT and a marked enhancement in the proliferative growth responsiveness of cultured PA-SMCs to 5-HT but not to other growth factors (Eddahibi, Humbert et al. 2001). Additional data suggested that the increased expression of 5-HTT in these patients is related to polymorphism of the 5-HTT gene promoter (Eddahibi, Humbert et al. 2001). A role for 5-HTT in experimental hypoxic pulmonary hypertension was also clearly established (Eddahibi, Hanoun et al. 2000). Therefore, 5-HT, notably through its specific transporter, appears as a key component in the pathogenesis of various types of human and experimental PH.
The 5-HTT can be competitively inhibited by specific drugs such as fluoxetine and paroxetine (de Jonghe and Swinkels 1997). Consequently, these drugs inhibit the in vitro proliferative response of SMC to 5-HT and also to a large extent the growth response to serum (Eddahibi, Humbert et al. 2001). However, their effects on PH development have not yet been investigated.
Primary pulmonary hypertension is characterized by increased pulmonary artery pressure and pulmonary vascular resistance. The hemodynamic derangement in primary pulmonary hypertension is an increased resistance to blood flow. Early in the disease the cardiac output is normal, however there is a noticeable elevation in pulmonary artery pressure. With time the cardiac output becomes diminished. At late stages in this disease the pulmonary capillary wedge pressure rises in response to impaired filling of the left ventricle due to an altered configuration of the intraventicular septum. To compensate for the depression in the right ventricular overload, the right atrial end-diastolic pressure rises.
As a result of the depression in the right ventricular septum, gradual onset of shortness of breath occurs in the individual inflicted with pulmonary hypertension. Other common symptoms associated with this disease include fatigue, angina pectoris, syncope, new syncope and peripheral oedema. The survival rate of individuals having pulmonary hypertension is about 2 to 10 years. The cause of death is generally right ventricular failure.
To treat this disease is very difficult. In the past it has been suggested to dramatically limit the individual's exercise coupled with diuretic therapy or vasodilator drugs. However, for example, with vasodilators a reduction in pulmonary vascular resistance may be obtained but in the long run a worsening in the right ventricular function occurs and thereby right ventricular failure occurs over time.
Moreover vasodilators can have acute and chronic adverse side effects. For instance, vasodilators can produce right ventricular ischemia resulting in death of an individual.
Although anticoagulant therapy has been suggested, there is no regression of the disease.
For individuals who have not responded to the radical drug treatment with the above-known vasodilators or anticoagulants, the only solution to the problem is heart-lung transplantation. The survival rate of such an operation is extremely short, i.e., less than 1 year.
Thus, it is an aspect of the present invention to provide a medical solution other than vasodilators, and anticoagulant therapy to prevent, attenuate or treat pulmonary hypertension.